Sleep disorders are a problem in a large portion of the population. Narcolepsy and insomnia are widely occurring. Safe, non-addictive and long-lasting drugs that are effective are substantially unavailable. Each class of drug currently used for this purpose has major drawbacks. For example, barbiturates have addictive tendencies, act as depressants on the central nervous system, and can be lethal in improper dosages. Benzodiazepines are less effective, and tend to lose their sedative effect with continued use. Gammahydroxybutyrate is effective in treatment of narcolepsy, and is a very powerful muscle relaxant, but is of only short duration of action, e.g. 2-3 hours. This is a major drawback, since the patient needs to be continually re-awakened for further dosages.
The present invention provides compounds and compositions for use in treatment of sleep disorders such as narcolepsy and insomnia, that will have sufficiently long duration of action to overcome this serious disadvantage. The chemical compounds correspond to the general formula: EQU R.CO.O.X.CO.O.R.sup.1
where X is a linear methylene chain of from 3-5 carbon atoms in length, R is selected from lower alkyl groups, aryl and aralkyl groups of 7-12 carbon atoms, and R.sup.1 is selected from lower alkyl groups and benzyl group.
Typical and preferred among the compounds used in the present invention is ethyl 4-acetoxybutanoate of formula: EQU CH.sub.3.CO.O.CH.sub.2.CH.sub.2.CH.sub.2.CO.O.C.sub.2 H.sub.5
Accordingly, the invention will be further described with reference to that specific compound.
From one aspect ethyl 4-acetoxybutanoate may be regarded as a chemically modified and chemically protected form of gammahydroxybutanoate, with the acid and hydroxyl functions thereof protected. Gammahydroxybutanoate has been demonstrated in clinical trials to be a safe, oral drug for treatment of narcolepsy and as a powerful muscle relaxant. However, its effects are of too short a duration, due to its lack of bio-availability. It is possible, that, after entry into the cell, the compound ethyl 4-acetoxybutanoate of the invention slowly hydrolyses to form gammahydroxybutanoate or a similar compound in situ, to exercise the therapeutic effects thereof over a longer period of time. In any event, it has been found that ethyl 4-acetoxybutanoate has a much longer lasting effect, at equivalent dosage levels, than gammahydroxybutanoate. This makes it a far more effective treatment for narcolepsy than anything heretofore available. Indeed, the effect is so markedly longer lasting that ethyl 4-acetoxybutanoate shows potential for treatment of patients having conditions or disorders where gammahydroxybutanoate is of little or no use. In cases of chronic insomnia, for example, sufficient dosages of the present compound can be administered to maintain sleep throughout the night, without incurring the development of tolerance or withdrawal side effects. Currently available chemotherapeutic agents will not do this. The compound of the present invention constitutes a safe and powerful hypnotic, for administration to a patient each night. The compound is also a powerful muscle relaxant for use in the treatment of a variety of conditions involving muscle spasticity.
In addition, there is evidence to suggest that ethyl 4-acetoxybutanoate inhibits the release of dopamine in the brain, indicating that it is potentially useful as an anti-Parkinsonian drug, an anti-schizophrenia drug, and an anti-psychosis drug in cases where the psychosis is associated with dopamine release and activity.
A large dose can have an extremely long duration of action (up to 12 hours) without toxic consequences. The duration of action can be controlled by the size of the dosage.
The drug ethyl 4-acetoxybutanoate according to the present invention may be compounded and administered in dosage levels similar to those commonly used for gammahydroxybutanoate (sodium oxybate, sold under the trade names "Anetamine" and "Somsanit"). Thus it may be orally administered as capsules, in admixture with the usual flavorants, excipients, carriers or the like. It may be taken orally as a solution or emulsion. It may be injected intraperitoneally or parenterally as a sterile buffered solution or emulsion e.g. in physiological saline. Amounts of the order of 10-100 mg per kilogram animal body weight, per nightly dosage, appears suitable in humans, with larger doses in animal use.
The compounds used in the present invention may be synthesized from the appropriate lactone, by reaction thereof with the appropriate alkanol, under acid condition. Thus, for the preparation of ethyl 4-acetoxybutanoate, butyrolactone is reacted with ethanol suitably in the presence of sulphuric acid. Similar procedures employing methanol instead of ethanol yields the methyl ester. An alternative synthesis involves the reaction of the appropriate carboxylic acid salt with a 4-halo-ester. Thus, by this procedure, ethyl 4-acetoxybutanoate may be prepared by reaction of ethyl 4-chlorobutanoate with acetic anhydride.
Alternative synthetic methods may be based on those in the published literature e.g.
Wright, "JACS", 63 1281 (1941); PA1 Meerwein, "Berichte" 89 2060 (1956).
The invention is further described and illustrated in the following specific examples.